Abstract Sudden Unexpected Death in Epilepsy (SUDEP) occurs in up to 50% of patients with refractory epilepsy and is the leading cause of death in this population. Because the mechanisms responsible for SUDEP have not been clearly defined, there are no specific treatments to prevent it. Recent observations from human and animal studies indicate that seizure-induced respiratory arrest typically precedes asystole, and that many patients experience varying degrees of respiratory depression following seizures. There is a fundamental gap in understanding how seizures depress respiration, and why some patients develop severe postictal respiratory depression and others do not. Low central CO2 chemosensitivity can contribute to respiratory depression, and it is possible that this predisposes to SUDEP, but has not been studied in this population. The long-term goal is to develop new treatments to prevent SUDEP by elucidating the mechanisms responsible for seizure-induced respiratory depression and by identifying biomarkers to identify patients at highest risk. The objective here is to characterize the relationship between CO2 chemosensitivity and postictal respiratory depression by measuring the slope of the hypercapnic ventilatory response (HCVR) in patients with epilepsy during the interictal and postictal states. The central hypothesis is that postictal hypoventilation will be more severe in patients with low interictal or postictal CO2 chemosensitivity. This hypothesis has been formulated based on human and animal data obtained from the applicants? own laboratories, data that also suggest serotonin (5-HT) defects may contribute to SUDEP. Because 5-HT neurons are known to be important for normal CO2 chemosensitivity that stimulates breathing and cortical arousal, the rationale for the proposed research is that defective chemo- sensitivity might contribute to the pathophysiology of SUDEP. The central hypothesis will be tested by pursuing 3 specific aims. (1) Determine the relationship between baseline (interictal) central CO2 chemosensitivity and postictal respiratory depression. (2) Determine how seizures affect central CO2 chemosensitivity. (3) Determine the stability of the HCVR over time in patients with epilepsy, and the relationship of the HCVR to epilepsy control. In Aims 1 and 2 patients admitted to the Epilepsy Monitoring Unit will undergo HCVR testing during the interictal and postictal periods. The slope of the baseline HCVR will be correlated with ictal changes in CO2 levels and other cardiorespiratory variables (Aim 1), and the effect of different seizures on HCVR slope will be measured (Aim 2). The intraindividual variability of the HCVR and its stability in relation to epilepsy control (Aim 3) will be determined by measuring the HCVR 4 times over 2 years. This approach is innovative because it is the first to directly examine the relationship between postictal ventilation and central CO2 chemosensitivity in the ictal and postictal states. The proposed research is significant because identifying the mechanisms involved in postictal respiratory depression may lead to identification of a novel biomarker (HCVR) for SUDEP risk and to development of new treatments designed to defend ventilation in the postictal period.